Nonmyeloablative Allografts in DLA-haploidentical Dogs: Engraftment and GVHD

DLA 单倍体狗的非清髓性同种异体移植：移植和 GVHD

• 批准号: 7478449
• 负责人: BRENDA MARIE SANDMAIER
• 金额: $ 41.46万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7478449
• 关键词: Allogenic; Allografting; Antibodies; Antigens; Autologous; Biological; Bismuth; Blood Cells; Breeding; CD45 Antigens; Canis familiaris; Cell Adhesion Molecules; Cell Transplantation; Cells; Chimeric Proteins; Chimerism; Clinical; Clinical Trials; Condition; Cyclosporine/Mycophenolate Mofetil; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Dose; Drug resistance; Engraftment; Genes; Goals; Grant; Granulocyte Colony-Stimulating Factor; HLA Antigens; Hematopoietic; High Dose Chemotherapy; Host vs Graft Reaction; Human; Immunoglobulins; Immunologics; Immunosuppressive Agents; Label; Leukocytes; Lymphocyte; Marrow; Mediating; Methotrexate; Monoclonal Antibodies; Natural Killer Cells; Patients; Pre-Clinical Model; Prevention; Principal Investigator; Radioisotopes; Range; Rate; Recovery; Residual state; Sirolimus; Stem cells; T-Lymphocyte; TNFSF5 gene; Tin; Toxic effect; Translating; Translations; Transplantation; Treatment Protocols; Work; cellular transduction; chemotherapy; graft vs host disease; graft vs host reaction; killer T cell; mycophenolate mofetil; programs; response; temozolomide

The long-term objective of this project is to develop a safe and reliable nonmyeloablative approach at hematopoietic cell transplantation (HCT) from dog leukocyte antigen (DLA)-haploidentical donors, which can be translated into clinical trials. The studies will focus on the bi-directional immunologic barriers, host-versus-graft (HVG) and graft-versus-host (GVH) reactions, which must be overcome in order to achieve both uniform and sustained hematopoietic engraftment and graft-host tolerance. Two goals were pursued during the current grant period. One included extension of work in DLA-identical littermates in which we successfully substituted monoclonal antibodies (MAbs) directed at either TCRalpha-beta or the ubiquitous hematopoietic antigen, CD45, which were labeled with an alpha-emitting radionuclide Bismuth-213 (213Bi), for 2 Gy TBI. We also established successful DLA-haploidentical grafts when recipients were treated first with an anti-CD44 antibody combined with 4.5 Gy TBI and then given mycophenolate mofetil (MMF) and cyclosporine (CSP) after HCT for control of residual HVG reactions and for GVHD prevention. However, when the TBI dose was decreased to the sublethal range of 2 Gy, the engraftment rate declined to 50%, while the remainder of the dogs eventually rejected their grafts and survived with autologous marrow recovery. Also, GVHD control, which is largely T-cell mediated, has not been uniform. The current proposal seeks to continue the studies on DLA-haploidentical grafts since development of safe approaches will expand the choice of potential donors. Two principal experimental approaches will be taken. One involves combining low-dose TBI with relatively non-toxic biological and pharmacological immunosuppressive agents, including 213Bi-labeled antibodies to natural killer (NK) cells, all aimed at reducing both host NK and T cell responses and T cell responsiveness of the graft. The other is to administer chemotherapy early after transplant to not only control GVHD but also facilitate engraftment. After we have determined the optimal tinning and dosing of posttransplantation chemotherapy, we will evaluate the use of donor cells transduced with drug resistance genes which will allow using higher doses of posttransplantation chemotherapy for both induction of donor chimerism and control of GVHD. GVHD prevention will also include control of donor lymphocyte replication with certain immunosuppressive agents, e.g., MMF and sirolimus, combined with blockers of T-cell costimulation. Our ultimate aim is to develop allogeneic HCT strategies for patients with alternative donors with the least short- and long-term toxicities, which can be successfully applied to human patients.

该项目的长期目的是在 来自狗白细胞抗原（DLA） - 帕克洛尼斯供体的造血细胞移植（HCT），可以 被翻译成临床试验。这些研究将重点放在双向免疫屏障，宿主与移植物上 （HVG）和移植物 - 宿主（GVH）反应，必须克服这两个反应才能达到同时实现 统一，持续的造血植入和移植宿主耐受性。在期间实现了两个目标 当前赠款期。其中一个包括我们在DLA认同的同窝室中的工作扩展。 成功取代针对tcralpha-beta或无处不在的单克隆抗体（mAb） 造血抗原CD45，用α发射放射性核素二核酸酯-213（213BI）标记 2 Gy TBI。我们还建立了成功的DLA-HAPLOIDENTIC移植物。 抗CD44抗体与4.5 Gy TBI结合，然后给出霉菌甲酸盐（MMF），并给予 HCT后，环孢素（CSP）控制残留的HVG反应和GVHD预防。然而， 当TBI剂量降低至2 Gy的范围时，植入率下降到50％， 剩下的狗最终拒绝了他们的移植物，并以自动骨髓生存 恢复。同样，很大程度上是T细胞介导的GVHD控制并不均匀。 当前的提议旨在继续对DLA-HAPLOIDECTIC移植物进行研究 安全的方法将扩大潜在捐助者的选择。两种主要实验方法将是 拍摄。其中一种涉及将低剂量TBI与相对无毒的生物学和药理学相结合 免疫抑制剂，包括对天然杀手（NK）细胞的213BI标记抗体，均针对 降低宿主NK和T细胞反应以及移植物的T细胞反应性。另一个是管理 移植后早期化学疗法不仅控制GVHD，还可以促进植入。之后我们有 确定移植后化学疗法的最佳修饰和剂量，我们将评估使用 用耐药性基因转导的供体细胞将允许使用更高剂量的移植后 化学疗法既诱导供体嵌合和GVHD的控制。 GVHD预防也将 包括控制供体淋巴细胞复制的某些免疫抑制剂，例如MMF和 Sirolimus，结合T细胞共刺激的阻滞剂。 我们的最终目的是为患有替代供体的患者制定同种异体HCT策略 最少的短期和长期毒性可以成功应用于人类患者。